The present invention relates generally to lymphokines, and specifically to use of particular lymphokines to promote differentiation and proliferation of hematopoietic stem cells.
Hemopoiesis refers to a process by which various mature blood cell types develop from developmentally multipotent stem cells found in hemopoietic, or blood-cell forming, tissues. These tissues are found in various body locations for example, bone marrow, spleen and thymus. In this process, distinct subpopulations of progenitor cells arise from more primitive, undifferentiated stem cells. Subsequent developmental events result in differentiation of mature classes of blood cells (for example, granulocytes, monocytes, eosinophils, megakaryocytes, and mast cells) from progenitor cell subpopulations.
Recent investigations of hemopoiesis have begun to elucidate the role of various hormone-like proteins or growth factors as effectors of hemopoiesis. Growth factors regulating early stages in the differentiation pathway are known collectively as multilineage growth factors. Those involved in later stages, wherein specialized cell types develop from precursor cells, are knwon as lineage-specific growth factors. Synergism between lineage-specific and multilineage growth factors appears to play a regulatory role in the ontogeny of blood cells.
Exemplary of such synergistic relationships are the joint activities of the growth factor heretofore designated hemopoietin-1 (H-1), and certain lineage-specific colony stimulating factors. H-1 is a multilinear growth factor identified by its capacity to induce development of multipotent stem cells in concert with other growth factors. In the absence of GM-CSF or other colony stimulating factor, H-1 exhibits no detectable effects in cultures of developmentally primitive hemopoietic cells. However, in the presence of GM-CSF, CSF-1, or certain other colony stimulating factors, H-1 stimulates cell growth and differentiation of hemopoietic cells more primitive than those capable of being induced by any of the colony stimulating factors alone. Preliminary characterization studies of hemopoietin-1 isolated from serum-free cultures of human bladder carcinoma cells and assayed in concert with CSF-1 a monocyte/macrophage lineage-specific growth factor, have been reported by Bartelmez et al., J. Cell. Phys. 122:370 (1985), Jubinski et al., Proc. Natl. Acad. Sci. USA 82:2764 (1985), and Stanley et al., Cell 45:667 (1986).
In view of the capacity of hemopoietin-1 to induce cell development at the earliest stages of hemopoiesis, considerable interest has developed in this growth factor as a therapeutic agent. Therapeutic utilities for a protein having the activity attributed to hemopoietin-1 include treatment of hematological anamalies resulting from chemotherapy, radiation treatment or exposure, exhancement of immune responses to viral or bacterial pathogens; treatment of leukemia; and use in conjunction with bone marrow transplants.
Interleukin-1 (IL-1) activity is attributable to proteins released by macrophages and other cell types in response to immunogenic stimulation. This family of proteins has been associated with a complex spectrum of biological activities. IL-1 is a primary immunostimulatory signal capable of inducing thymocyte proliferation via induction of interleukin-2 release, and stimulating proliferation and maturation of B-lymphocytes. In addition, IL-1 has been linked with prostaglandin production and induction of fever, and with promotion of wound healing. Useful reviews of the literature relating to IL-1 include Oppenheim at al., Immunol. Today 7:45 (1986), and Durum et al., Ann. Rev. Immunol. 3:263 (1985).
Prior to the present invention, IL-1 had not been observed to exhibit activity as a multilineage hemopoietic growth factor. The present invention resides in the unexpected discovery that the biological activity of IL-1, in concert with GM-CSF, is coincident with that of the growth factor heretofore termed hemopoietin-1. Further, physicochemical and serological criteria indicate that IL-1 and hemopoietin-1 are identical. This discovery was facilitated by recent inventions which enabled production of useful quantities of substantially homogeneous recombinant human IL-1.